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Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt-Jakob disease

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Abstract

We have compared the immunomorphological spectrum of the deposition of the disease-associated prion protein (PrPSc) in the cerebral and cerebellar cortex of 32 Creutzfeldt-Jakob disease (CJD) patients with the PrP gene (PRNP) E200K mutation to 45 sporadic CJD and 14 other genetic prion disease cases. PrP deposits correlate with the genotype at the methionine/valine (MV) polymorphic codon 129. While the diffuse/synaptic and patchy/perivacuolar PrP deposits and PrP plaques have a similar distribution and correlation with the genotype at codon 129 as in sporadic CJD, an additional peculiar PrP immunostaining pattern occurs in the cerebellum in 81% E200K mutation brains including 93% of M129M, 71% of M129V, but not in the single V129V case. It is localized to the molecular layer and consists of coarse granular PrP deposits arranged in a stripe-like manner predominantly perpendicular to the surface, closely resembling the parasagittal arborization of climbing fibers. Our results suggest that (1) the type of PrP deposits in the cerebellum may suggest genetic disease and the need for genetic testing; and (2) the peculiar stripes of PrP deposits might reflect selective vulnerability of cerebellar structures.

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References

  1. Almer G, Hainfellner JA, Brucke T, Jellinger K, Kleinert R, Bayer G, Windl O, Kretzschmar HA, Hill A, Sidle K, Collinge J, Budka H (1999) Fatal familial insomnia: a new Austrian family. Brain 122:5–16

    Article  PubMed  Google Scholar 

  2. Bell JE, Gentleman SM, Ironside JW, McCardle L, Lantos PL, Doey L, Lowe J, Fergusson J, Luthert P, McQuaid S, Allen IV (1997) Prion protein immunocytochemistry—UK five centre consensus report. Neuropathol Appl Neurobiol 23:26–35

    PubMed  Google Scholar 

  3. DeArmond SJ, Qiu Y, Sanchez H, Spilman PR, Ninchak-Casey A, Alonso D, Daggett V (1999) PrPc glycoform heterogeneity as a function of brain region: implications for selective targeting of neurons by prion strains. J Neuropathol Exp Neurol 58:1000–1009

    CAS  PubMed  Google Scholar 

  4. Ghetti B, Piccardo P, Frangione B, Bugiani O, Giaccone G, Young K, Prelli F, Farlow MR, Dlouhy SR, Tagliavini F (1996) Prion protein amyloidosis. Brain Pathol 6:127–145

    CAS  PubMed  Google Scholar 

  5. Hainfellner JA, Parchi P, Kitamoto T, Jarius C, Gambetti P, Budka H (1999) A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein. Ann Neurol 45:812–816

    Article  CAS  PubMed  Google Scholar 

  6. Inoue I, Kitamoto T, Doh-ura K, Shii H, Goto I, Tateishi J (1994) Japanese family with Creutzfeldt-Jakob disease with codon 200 point mutation of the prion protein gene. Neurology 44:299–301

    CAS  PubMed  Google Scholar 

  7. Kitamoto T, Doh-ura K, Muramoto T, Miyazono M, Tateishi J (1992) The primary structure of the prion protein influences the distribution of abnormal prion protein in the central nervous system. Am J Pathol 141:271–277

    CAS  PubMed  Google Scholar 

  8. Kovacs GG, Head MW, Bunn T, Laszlo L, Will RG, Ironside JW (2000) Clinicopathological phenotype of codon 129 valine homozygote sporadic Creutzfeldt-Jakob disease. Neuropathol Appl Neurobiol 26:463–472

    PubMed  Google Scholar 

  9. Kovacs GG, Head MW, Hegyi I, Bunn TJ, Flicker H, Hainfellner JA, McCardle L, Laszlo L, Jarius C, Ironside JW, Budka H (2002) Immunohistochemistry for the prion protein: comparison of different monoclonal antibodies in human prion disease subtypes. Brain Pathol 12:1–11

    PubMed  Google Scholar 

  10. Lee HS, Sambuughin N, Cervenakova L, Chapman J, Pocchiari M, Litvak S, Qi HY, Budka H, Ser T del, Furukawa H, Brown P, Gajdusek DC, Long JC, Korczyn AD, Goldfarb LG (1999) Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease. Am J Hum Genet 64:1063–1070

    Article  CAS  PubMed  Google Scholar 

  11. Mayer V, Mitrova E, Orolin D (1979) Creutzfeldt-Jakob disease in Czechoslovakia and a working concept of its surveillance. In: Prusiner SB Hadlow J (eds) Slow transmissible diseases of the nervous system. Academic Press, New York, pp 287–303

  12. Mitrova E, Mayer V, Orolin D (1978) Transmissible virus dementia. II. Neurohistology of three, geographically clustered cases of Creutzfeldt-Jakob disease. Acta Virol 22:154–161

    CAS  PubMed  Google Scholar 

  13. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233

    PubMed  Google Scholar 

  14. Parchi P, Zou W, Wang W, Brown P, Capellari S, Ghetti B, Kopp N, Schulz-Schaeffer WJ, Kretzschmar HA, Head MW, Ironside JW, Gambetti P, Chen SG (2000) Genetic influence on the structural variations of the abnormal prion protein. Proc Natl Acad Sci USA 97:10168–10172

    Article  CAS  PubMed  Google Scholar 

  15. Prusiner SB (1997) Prion diseases and the BSE crisis. Science 278:245–251

    CAS  PubMed  Google Scholar 

  16. Sarna J, Miranda SR, Schuchman EH, Hawkes R (2001) Patterned cerebellar Purkinje cell death in a transgenic mouse model of Niemann Pick type A/B disease. Eur J Neurosci 13:1873–1880

    Article  CAS  PubMed  Google Scholar 

  17. Schulz-Schaeffer WJ, Giese A, Windl O, Kretzschmar HA (1996) Polymorphism at codon 129 of the prion protein gene determines cerebellar pathology in Creutzfeldt-Jakob disease. Clin Neuropathol 15:353–357

    Google Scholar 

  18. Seno H, Tashiro H, Ishino H, Inagaki T, Nagasaki M, Morikawa S (2000) New haplotype of familial Creutzfeldt-Jakob disease with a codon 200 mutation and a codon 219 polymorphism of the prion protein gene in a Japanese family. Acta Neuropathol 99:125–130

    CAS  PubMed  Google Scholar 

  19. Strata P, Tempia F, Zagrebelsky M, Rossi F (1997) Reciprocal trophic interactions between climbing fibres and Purkinje cells in the rat cerebellum. Prog Brain Res 114:263–282

    CAS  PubMed  Google Scholar 

  20. Tranchant C, Geranton L, Guiraud-Chaumeil C, Mohr M, Warter JM (1999) Basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Neurology 52:1244–1249

    CAS  PubMed  Google Scholar 

  21. Vital C, Gray F, Vital A, Parchi P, Capellari S, Petersen RB, Ferrer X, Jarnier D, Julien J, Gambetti P (1998) Prion encephalopathy with insertion of octapeptide repeats: the number of repeats determines the type of cerebellar deposits. Neuropathol Appl Neurobiol 24:125–130

    Article  CAS  PubMed  Google Scholar 

  22. Voogd J, Glickstein M (1998) The anatomy of the cerebellum. Trends Neurosci 21:370–375

    CAS  PubMed  Google Scholar 

  23. Voogd J, Ruigrok TJ (1997) Transverse and longitudinal patterns in the mammalian cerebellum. Prog Brain Res 114:21–37

    CAS  PubMed  Google Scholar 

  24. Windl O, Dempster M, Estibeiro JP, Lathe R, Silva R de, Esmonde T, Will R, Springbett A, Campbell TA, Sidle KC, Palmer MS, Collinge J (1996) Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Hum Genet 98:259–264

    Article  CAS  PubMed  Google Scholar 

  25. Wong NK, Renouf DV, Lehmann S, Hounsell EF (2000) Glycosylation of prions and its effects on protein conformation relevant to amino acid mutations. J Mol Graph Model 18:126–134, 163–165

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Austrian Fund for Scientific Research (FWF, No. P14584-PSY), and belongs to the framework of an EU-funded project "Human TSEs: the neuropathology network (PRIONET)" (project leader: H. Budka). We are grateful to Helga Flicker and Ulrike Köck for excellent technical work. Statistical analysis was performed by Peter Birner.

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Authors and Affiliations

  1. Institute of Neurology, University of Vienna and Austrian Reference Center for Human Prion Diseases, AKH 4J, Währinger Gürtel 18–20, POB 48, 1097, Vienna, Austria

    Christa Jarius, Gabor G. Kovacs, Johannes A. Hainfellner & Herbert Budka

  2. Research Institute of Preventive Medicine, Bratislava, Slovakia

    Girma Belay & Eva Mitrova

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  1. Christa Jarius
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  2. Gabor G. Kovacs
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  3. Girma Belay
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  4. Johannes A. Hainfellner
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  5. Eva Mitrova
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  6. Herbert Budka
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Correspondence to Herbert Budka.

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The first two authors contributed equally to this work

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Jarius, C., Kovacs, G.G., Belay, G. et al. Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt-Jakob disease. Acta Neuropathol 105, 449–454 (2003). https://doi.org/10.1007/s00401-002-0664-z

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  • DOI: https://doi.org/10.1007/s00401-002-0664-z

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